Effects of IGFBP-1 and IGFBP-2 and their fragments on migration and IGF-induced proliferation of human dermal fibroblasts

- IGFBP-1 and -2 and fragments, after cleavage by azurocidin, stimulated HDF migration.
- IGFBP-1 increased phosphorylation of FAK and ERK1/2.
- The above results were abolished by pre-treating HDFs with an α5β1 integrin antibody.
- IGFBP-1, IGFBP-2 or fragments increased HDF migration in high glucose.
- IGFBP-1 and -2 and fragments differentially modulate HDF proliferation.

ObjectiveA family of six insulin-like growth factor (IGF) binding-proteins (IGFBP) bind to IGF-I and IGF-II with high affinity and modulate their activity. We have recently shown that a neutrophil-derived protease activity cleaved IGFBP-1, -2 and -4. IGFBP-1 and IGFBP-2 have a C-terminal Arg-Gly-Asp (RGD) sequence, and IGFBP-1 has been shown by others to stimulate migration through binding of its RGD sequence to α5β1 integrin. The aim of this study was to determine the effect of this IGFBP protease on IGF-induced proliferation and the effect of IGFBP-1 and IGFBP-2 and their proteolytic fragments on migration in normal and high glucose of human dermal fibroblasts (HDF).DesignWe investigated the effect of intact or cleaved IGFBP-1 and -2 on proliferation in cultured HDFs and on HDF migration in normal and high glucose.ResultsBoth IGFBP-1 and IGFBP-2 and their proteolytic fragments stimulated HDF migration and the stimulatory effect was abolished by pre-treating cells with a α5β1 integrin antibody. High glucose impaired migration of HDFs; however, the addition of IGFBP-1, IGFBP-2 or fragments increased migration to levels observed in normoglycemia.IGFBP-2 inhibited IGF-II induced proliferation; however, the inhibitory effect was reduced after being cleaved. Intact native IGFBP-1 showed either potentiating or inhibitory effects on IGF-I induced proliferation depending on the confluence of cells, and proteolysis of IGFBP-1 did not change these effects. IGFBP-1 was found to increase phosphorylation of FAK and ERK1/2 and this effect was inhibited by the monoclonal integrin a5β1 ab.ConclusionsIGFBP-1 and -2 and their proteolytic fragments may improve tissue repair under inflammatory conditions, through effects on proliferation and migration of HDFs in normal and high glucose.